Investigating MUC1/ICAM-1 Binding Induced Signaling in Breast Cancer Metastasis
Anuual summary 1 May 2010-30 Apr 2011
ALBERTA UNIV EDMONTON
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Breast cancer is the second leading cause of cancer death in Canadian women. To metastasize, cells must move through the stroma of the breast, enter the circulation, survive transit, exit the circulation, and form a secondary tumor. It is not fully understood how breast cancer cells gain the ability to move or what signaling pathways mediate these events, and identification of critical components of these pathways would represent potential targets for anti-metastatic therapies. The MUC1 glycoprotein is expressed on the apical membrane of normal breast epithelia. In many human breast carcinomas, MUC1 is overexpressed and loses apical polarization, events that correlate with increased metastasis. Several critical steps of the metastatic cascade require cell adhesion, and it has been reported that MUC1 is a ligand for ICAM-1, which is expressed throughout the migratory tract of a metastasizing breast cancer cell. It was subsequently reported that MUC1ICAM-1 binding initiates calcium oscillations, cytoskeletal reorganization, and cell migration, suggesting that binding could be important in metastasis. Here, we investigate the mechanism of MUC1ICAM-1 binding induced signaling. We show that MUC1 forms constitutive dimers which are required for Src recruitment and ICAM-1 binding induced signaling. We show that MUC1 dimers are not covalently linked and do not require cytoplasmic domain cysteine residues. These results reveal information on the mechanism of MUC1ICAM-1 signalling, which can be used to identify novel targets and combinational strategies for anti-metastatic therapy in breast cancer.
- Anatomy and Physiology
- Medicine and Medical Research